thyrotoxicperiodicparalysis:casereportsand anup-to ...thyrotoxic periodic paralysis (tpp) is one of...

Hindawi Publishing CorporationCase Reports in EndocrinologyVolume 2011, Article ID 867475, 4 pagesdoi:10.1155/2011/867475

Case Report

Thyrotoxic Periodic Paralysis: Case Reports andan Up-to-Date Review of the Literature

Abbi Lulsegged,1 Christina Wlodek,1 and Michela Rossi2

1 Department of Endocrinology, South London HealthCare NHS Trust, Orpington Hospital, Sevenoaks Road,Orpington BR6 9JU, UK

2 Department of Endocrinology, Whittington NHS Trust Hospital, London N19 5NF, UK

Correspondence should be addressed to Abbi Lulsegged, [email protected]

Received 4 June 2011; Accepted 20 July 2011

Academic Editors: G. Aimaretti, K. Kasagi, L. Meyer, and W. V. Moore

Copyright © 2011 Abbi Lulsegged et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. To describe 2 cases of thyrotoxic periodic paralysis. Methods. We report of 2 cases of thyrotoxic periodic paralysis in2 individuals from 2 different backgrounds with emphasis on their presentation and treatment. We also conducted a literaturesearch to put together an update review of thyrotoxic periodic paralysis. Results. A 47-year-old Chinese and 28-year-old Caucasianmale presented with profound yet reversible weakness associated with hypokalemia on admission bloods and thyrotoxicosis. Bothwere given definitive therapy to prevent recurrence of attacks with any future relapse of thyrotoxicosis. Conclusion. Thyrotoxicperiodic paralysis (TPP) is a rare but potentially serious complication of thyrotoxicosis resulting in temporary but severe muscleweakness. Recent discovery of a novel mutation in the KCNJ18 gene which codes for an inwardly rectifying potassium channel andis controlled by thyroid hormones may provide greater insight into the pathogenesis of TPP.

1. Introduction

Thyrotoxic periodic paralysis (TPP) is the most commoncause of acquired hypokalaemic periodic paralysis. This con-dition is often transient but potentially serious. It is classicallyassociated with thyrotoxicosis and hypokalemia. Prompt rec-ognition of the problem allows for proper short- and long-term management of this condition.

2. Case Reports

A 47-year-old Chinese gentleman presented acutely with aone week history of lower limb weakness and a three-hourhistory of total lower limb paralysis on wakening. He alsocomplained of palpitations over the previous year. He deniedany family history of thyroid or neurological problems. Thelower limb weakness had resolved by the time he was seen inhospital.

On examination his upper and lower limb power was 5/5throughout with no fatigable weakness. Cardiovascular, pul-monary, and abdominal examinations were unremarkable.He was clinically euthyoid with no tremor, nail changes, or

thyroid eye signs. There was no palpable goitre. His serumpotassium on admission was 3.1 mmol/L, free thyroxine (T4)level 38.5 pmol/L (9.4–22.7), free triiodothyronine (T3) level14.4 pmol/L (3.5–6.5), and TSH < 0.01 mU/L (0.35–5.50).ECG showed sinus tachycardia only.

He was given carbimazole 40 mg daily, propranolol, po-tassium iodide, and lithium so as to promote a rapid euthy-roid state and thereby allow for a thyroidectomy which hehad several weeks later. A thyroidectomy was performedrather than administration of radioactive iodine because itwould have been very difficult for the patient to attend forthe blood tests and follow-up appointments required afterradioactive iodine.

The second case involved a 28-year-old Caucasian gen-tleman who presented with nocturnal leg weakness, pain inthe muscles of both legs and proximal arms. He awoke themorning of his admission with profound leg weakness andcould not get out of bed. He had flaccid weakness of the armsand legs and generalised hyperreflexia. Urgent electromyog-raphy and nerve conduction studies were normal. His serumpotassium was 2.6 mmol/L, TSH < 0.01, fT4 54 pmol/L (12–22) and TSH receptor antibodies were elevated consistent

2 Case Reports in Endocrinology

with Graves’ disease and thyrotoxic periodic paralysis. Hewas started on propranolol 20 mg twice daily, carbimazole40 mg daily and subsequently had radioactive iodine.

3. Discussion

Thyrotoxic periodic paralysis (TPP) is one of the causes ofhypokalemic paralysis (HP). HP is a condition character-ised by muscle weakness associated with changes in potas-sium levels. HP can occur either due to transient shifts (hy-pokalemic periodic paralysis or HPP) or reduction in abso-lute potassium levels (nonhypokaelmic periodic paralysis)[1].

Familial cases are inherited in an autosomal dominantmanner. Mutations in CACNA1S and SCN4A gene adverselyaffect the function of calcium and sodium ion channelsservicing muscle cells, respectively [2]. The KCNJ2 genecodes for inward rectifying potassium channels (Kir 2.1) thatmoves potassium ions into the cells of skeletal and cardiacmuscles. Mutations of this gene have been known to causefamilial periodic paralysis with arrhythmias and Andersen-Tawil syndrome [3, 4].

Young Oriental men are more likely to be affected witha prevalence of around 2% of all thyrotoxic cases comparedto 0.2% in thyrotoxic Caucasian patients [5]. However thiscondition can affect individuals from different parts of theworld [6, 7].

It can present as a medical emergency. Patients often havean abrupt onset of paralysis which could affect all four limbstraditionally associated with hypokalaemia. Suspected casesof TPP with normal potassium levels during an attack havebeen reported although it is worth noting that techniques fortaking blood may lead to spuriously higher levels of potas-sium [8]. The classical presentation is of ascending lowerlimb paralysis in the early hours of the morning, or after restfollowing strenuous exercise and a high carbohydrate meal,leaving the patient unable to move. Acute episodes may bepreceded with muscle aches, cramps, or stiffness. It is rareto observe ocular, bulbar, or respiratory muscle involvement.Tendon reflexes are generally diminished or absent (althoughthe patient in our second case report had hyperreflexia) withintact sensation and consciousness [9].

Attacks are typically transient and last hours to days andmay be triggered by a number of conditions. These includecarbohydrates—especially refined carbohydrates and afterexercise. Other precipitating factors include trauma, expo-sure to hot weather, upper respiratory tract infections, emo-tional stress, menses, medications (diuretics, insulin, gluco-corticosteroids, and acetazolamide), alcohol, or recreationaldrugs such as 3,4-Methylenedioxymethamphetamine (ecsta-sy) [10–13]. Table 1 summarises the important triggers.

The Na/K+/ATPase pump located on the sarcolemma ofmuscle cells prevents accumulation of intracellular sodium.It pumps out 3 Na+ for every 2 K+ ions it pumps into the cell.The influx of potassium into the cells alters the resting poten-tial of the muscle cell leaving it unable to depolarise because itis hyperpolarised. The pump is activated by catecholamines(via beta-2 receptors) and therefore in susceptible patients,thyroid hormones since they sensitise the circulation to

circulating catecholamines. Thyroid hormones can alsodirectly stimulate Na/K/ATPase activity, and thyrotoxicosis(with or without periodic paralysis) has been shown to in-crease pump numbers [14, 15]. This pump is also activatedby androgens, and men are approximately 10–20 times morelikely to be affected than women, with onset in the 4-5th dec-ade of life [16].

Insulin activates the Na+/K+/ATPase pump causing aninflux of potassium into cells and thus anything that pro-motes hyperinsulinaemia such as high glycaemic and/or re-fined carbohydrates can trigger or exacerbate the underlyingproblem. Euglycaemic hyperinsulinaemic clamp studies haveshown that patients with thyrotoxic periodic paralysis maybe more insulin resistant than age/sex-matched controls andtherefore more likely to have hyperinsulinaemia [17]. Thecombination of hyperinsulinaemia and TPP is associatedwith increased Na/K/ATPase activity [18].

As always a detailed clinical history and thorough clinicalexamination may reveal clues. Thyrotoxic features maybe ab-sent or very subtle; therefore the clinician must have a highindex of suspicion [19].

A spot urine test for electrolytes and potassium excretioncan be very useful. Normal acid base status and low urinarypotassium levels are characteristic of hypokalaemia in TPP. Itis also important to appreciate that serum potassium levelsmay be normal in between attacks. Transient hypophospha-temia and hypomagnesemia have been documented along-side elevated creatine phosphokinase. These disturbancesresolve as the underlying thyrotoxicosis is treated. Further-more some authors have suggested that measuring the uri-nary calcium/phosphate ratio may help diagnose this oth-erwise rare condition since thyrotoxicosis is associated withincreased urinary calcium excretion and TPP with hypo-phosphataemia [20].

Thyrotoxic periodic paralysis, as the name suggests, isassociated with thyrotoxicosis. Any cause of thyrotoxicosismaybe sufficient to trigger attacks in susceptible patients.Indeed the condition has been reported in one patient withhypothyroidism who was overreplaced with thyroxine and inanother who took triiodothyronine (T3) to facilitate weightloss [21, 22]. The serum thyroid-stimulating hormone levelis low or suppressed accompanied by raised free thyroxine(fT4) and triiodothyronine (fT3) levels consistent with pri-mary thyrotoxicosis. Rarely some patients may have centralthyrotoxicosis in which case the TSH is detectable and asso-ciated with elevated fT4 and fT3 levels [23]. Milder forms ofthyrotoxicosis have been associated with thyrotoxic periodicparalysis adding to the diagnostic difficulties [24].

An electrocardiogram may show characteristic features ofhypokalaemia. Unlike hypokalaemia from other causes, sinustachycardia predominates in TPP patients. Other findings in-clude atrial fibrillation, atrioventricular block, ventricular fi-brillation, and asystole [25, 26]. The electrolyte disturbancecan be severe enough to cause asystole and cardiac arrest [27].

The underling hyperthyroid state has to be addressed inorder to definitively rectify the condition; however initiallypotassium replacement maybe needed to hasten muscle re-covery and prevent cardiopulmonary complications [28].Potassium chloride is the preferred salt as its is less irritant

Case Reports in Endocrinology 3

Table 1: Triggers of periodic paralysis attacks.

Triggers Examples Notes

High glycaemic index foodsSweetened drinks, pasta, certain fruits, whitebread, certain cereals and fruits, forexample, watermelon, rice, potatoes

High glycaemic index foods promote releasehigher insulin levels

Salt/high sodium intake High-salt-containing foods Promotes diuresis and loss of potassium.

Stresses Infection, psychological, surgeryRelease of catecholamines which canactivate Na/K/ATPase pump

Ambient temperature Cold weather.

Physical activity Rest after significant exertionWeakness maybe apparent first thing in themorning

Gastrointestinal Diarrhoea. Loss of potassium

Drugs

Acetazolamide, oestrogen, diuretics,laxatives, liquorice, cortisol,aminoglycosides, acrolides,fluoroquinolones

Listed antibiotics adversely affectneuromuscular transmission

Liquorice and cortisol promote potassiumexcretion

Oestrogen can increase insulin resistance

[29]. Supplementation must be given with caution (not fasterthan 10 mmol/hour) as there is a risk of rebound hyper-kalemia once the muscle cells recover releasing potassiumand phosphate into the circulation [30]. For this reason wewould recommend using potassium supplementation (espe-cially intravenously) for those patients or at risk of cardiopul-monary arrest.

A nonselective beta blocker such as propanolol can rap-idly promote recovery without the risk of rebound hyper-kalaemia [31]. Propranolol blunts the hyperadrenergic stim-ulation of the Na-K-ATPase pump [32]. Patients should beeducated to avoid precipitating factors and continue propra-nolol until a euthyroid state is achieved so as to preventsymptoms.

Antithyroid medication and thyroidectomy or radioio-dine therapy are mandatory to secure a complete cure ofTPP and prevent recurrence. There has been a case report ofradioactive iodine use being associated with early recurrenceof TPP—radioactive iodine can be associated with transientthyroiditis/hyperthyroidism [33]. Therefore caution is rec-ommended if radioactive iodine is chosen as the method ofdelivering definitive treatment and should perhaps be avoid-ed if the patient has or is at risk of cardiovascular disease orhad a history of significant arrhthymias.

Phenotypically TPP resembles familial hypokalaemic pe-riodic paralysis, which is a channelopathy. A hypothesis sur-rounding this similarity recently led to the discovery of mu-tations of an inwardly rectifying potassium (Kir) channelKir2.6. It is expressed in skeletal muscle and is transcrip-tionally regulated by thyroid hormone. The gene KCNJ18was discovered to code for this Kir2.6 channel which pro-motes a greater influx of potassium into the cells. Kir2.6 mu-tations were discovered to be present in 25–33% of unrelatedTPP patients in a recent study [34]. Some of these mutationsaltered a number of Kir2.6 properties and hence musclemembrane excitability leading to paralysis. Kir channelopa-thies contribute to a number of human diseases includingepisodic muscle and developmental features of Anderson-

Tawil syndrome (Kir2.1), the renal tubular secretion defectsof Bartter syndrome type III (Kir1.1), and defective insulinsecretion in persistent hyperinsulinemic hyperglycemia ofinfancy (Kir6.2).

Through electrophysiological tests, Ryan et al. revealedthat some of the Kir2.6 mutations have large effects oncurrents either inherently or via thyroid hormone induciblemechanisms, such that these mutations may cause predispo-sition for episodic weakness seen only during thyrotoxicosis[34]. This genetic test is not yet carried out in the UK,therefore our patient was not tested for a mutation of Kir2.6.

In summary this recent finding has affirmed the complexand widespread role of thyroid hormones in metabolicfunction and more specifically in TPP. It has also uncoveredat least one type of genetic predisposition for the condition.This channelopathy confirms the importance of consideringTPP in a patient with sudden onset weakness or paral-ysis associated with hypokalaemia and should make onespecifically search for signs and symptoms of thyrotoxicosis.Failure to quickly identify the diagnosis as TPP can befatal, but efficient correction of potassium as well as thehyperthyroid state can resolve symptoms rapidly and preventcomplications. Furthermore the discovery of a mutation inKCNJ18 gene may well provide us with greater insight intothe pathophysiology of thyrotoxic periodic paralysis with aview to better managing the condition.

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4 Case Reports in Endocrinology

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